Nu-alkyl-pyrrolidine-2-methanol, alpha cyclohexyl mandelates



United States Patent This invention relates to basic esters and to theiracid addition and quaternary salts.

The present invention provides new compounds of the general formula:

where R is an alkyl group having from 1 to 4 carbon atoms and n is l, 2,3 or 4, and acid addition and quaternary salts thereof.

phenylcyclohexylglycollate methobromide has been shown to possessparticularly useful properties as a spasmolytic, especially in that itseffect is remarkably long-lasting.

Since the compounds of the present invention contain asymmetric centresthey can exist in several optically active forms and the presentinvention extends to these optically active forms as Well as to thecorresponding racernic mixtures. For example, the hydrochloride of(l-methyl-Z pyrrolidyl)methyl phenylcyclohexylglycollate isseparable,'by crystallisation from suitable solvents, into two opticallyinactive (EL) forms. Both of these forms may be converted intoquaternary derivatives having the same desirable long-lastingspasmolytic properties.

The present invention also provides a process for the preparation ofcompounds of thegeneral Formula l, in which an ester of the generalformula:

where R is an alkyl group having from 1 to 4 carbon atoms (especially amethyl group) is reacted with an alcohol or the general formula:

R (III) Where R is an alkyl group having from 1 to 4 carbon atoms and nis 1, 2, 3 or 4. This reaction can convenient- 1y be achieved by heatingthe reactants in a suitable solvent, e.g. light petroleum or n-heptane,in the presence .of a small proportion of an alkali metal alkoxide, for

example a sodium a l-toxide such as sodium methoxide.

The present invention also includes a process for the preparation ofcompounds of the general Formula I, in

3,ll?,9ld Patented Jan. 14, 1954 'ice which an alcohol of the generalFormula Ill is reacted with phenylcyclohexylchloracetyl chloride and theresultant product treated with water and a base.

The present invention further provides a process for the preparation ofcompounds of the general Formula I, in which phenylcyclohexyl glycollicacid is reacted with an alkyl halide of the general formula:

where R is an alltyl group having from '1 to 4 carbon atoms, 12 is 1, 2,3 or 4 and X is an atom of chlorine or bromine, to form a'compound ofthe general formula:

which is then converted-into a compoundof-the general Formula I, forexample by treatment withabase.

Alternatively, the phenylcyclohexyl glycollic acid in the processdescribed above can be replaced by one of its salts, preferably a saltof an alkali metal, for example sodium, and when this is done a compoundof the general Formula l is obtained directly and not, as describedabove, in the form of a hydrohalide salt. In practice, a-hydrohalidesalt is often more desirable'than the corresponding free base and thusit is usually preferable to use theprocess which provides thehydrohalide salt directly.

The anion of the salts of this invention can be chosen from any of theusually acceptable anions, for'example, halide, sulphate, citrate ortartrate, the choice depending to a large extent upon pharmaceuticalconvenience and the physical properties which it is desired the salt topossess, for example, stability or solubility. Of course, toxic anions,for example the oxalate ion, should be avoided. Where the salt is anacid addition salt derived from an organic acid it is preferablyprepared by treating the corresponding free base with the appropriateorganic acid in a suitable solvent.

The quaternary salts of-this invention can readily be obtained from thecompounds of the general Formula I by conventional means. Quaternarysalts derived from organic acids can be prepared directly from thecorrespondinghalide salt by treating the latter with the silver salt ofthe appropriate organic acid.

The foliov 'ing examples illustrate the invention:

Example 1 This example describes the preparation of (l-methyl-2-pyrrolidyl)methyl phenylcyclohexylglycollate hydrochloride and itsseparation into two (DID-forms.

with Water (3 X 50 1111.), was extracted with 5N hydrochloric acid (3 x1111.). The hydrochloride (3 5.5 g., 71%) crystallised out of the acidextract as colourless needles, Ml. l81-l96 C. Extraction of thishydrochloride (33 g.) with hot ethanol ml.) left the 3 sparingly soluble(1-methyl-2-pyrrolidyl)methyl phenylcyclohexylglycollate hydrochloride(ea-form) (7.6 g.) M.P. 220222 C. as a residue. The readily soluble (1-methyl 2 pyrrolidyl)methyl phenylcyclohexylglycollate hydrochloride(ii-form) (22 g.), M.P. l99201 C., was obtained from the ethanol extracton cooling.

The 1-methyl-2-hydroxymethylpyrrolidine used in this example wasprepared as follows:

To an ethanolic solution of methylamine (200 g. of 33% w./v.corresponding to 6 mols.) in a flask fitted with a brine condenser andcarbon dioxide/ acetone trap, was added dibromoamyl acetate (100 g.).After some 10 minutes a vigorous reaction took place and the reactionboiled. When this initial reaction had subsided the mixture was heatedunder reflux for 6 hours. The alcohol was distilled off at atmosphericpressure and sodium hydroxide solution was added (120 mil. of 25%), themixture heated for a further hour and then extracted continuously withether. The ether after drying with magnesium sulphate was removed andthe residue fractionally distilled under reduced pressure to givel-methyl-Z-hydroxymethylpyrrolidine.

Example 2 This example describes the preparation of (1-methyl-2-pyrrolidyl)methyl phenylcyclohexylglycollate hydrochloride by analternative route.

1-Methyl-Z-hydroxymethylpyrrolidine g.) in dry butanone ml.) was addedto a solution of phenylcyclohexylchloroacetyl chloride (13 g.) in drybutanone ml.) and the mixture refluxed for 1 hour. The solvent was thenremoved in vacuo and the residue dissolved in water. The aqueoussolution after extraction with ether (2 x ml.) was heated on a steambath at 85 C. for 1 hour and then cooled to give a solid which wasfiltered ofi, washed with water and dried. The yield of hydrochloridewas 7 g. (44%), M.P. 194208 C.

The phenylcyclohexylchloroacetyl chloride used in the above example wasprepared by the action of phosphorous pentachloride onphenylcyclohexylglycollic acid. The lmethyl-Z-hydroxymethylpyrrolidinewas prepared as described in Example 1.

Example 3 This example describes the preparation of (l-methyl- 2pyrrolidyl)methy1 phenylcyclohexylglycollate hydrochloride by a furtheralternative method.

A solution of phenylcyclohexylglycollic acid (13.8 g.) and1-methyl-2-chloromethylpyrrolidine (8.6 g.) in dry isopropanol (15 ml.)was refluxed for 24 hours. On cooling the mixture(l-methyl-Z-pyrrolidyl)methyl phenylcyclohexylglycollate hydrochloride(8.3 g., 39%), M.P. 193-200" C., separated out.

The 1-methyl-2-chloromethylpyrrolidine used in this example was obtainedas a colourless liquid, B.P. 4546 C./ 14 mm. by the action of thionylchloride on l-methyl- 2-hydroxymethylpyrrolidine. The latter wasobtained as described in Example 1.

Example 4 This example describes the preparation of (l-methyl-2-pyrrolidyl)methyl phenylcyclohexylglycollate methobromide from thehydrochlorides described in Example 1.

(a) The ester hydrochloride (mixed isomers, M.P. 181196 C., 15 g.) wasdissolved in Water, basified with sodium hydroxide solution and theresultant oil extracted into ether. The extracts were dried overmagnesium sulphate, the ether evaporated and the residue dissolved inacetone (100 ml.). Methyl bromide (7.8 g., 2 mole) was added to theacetone solution and the mixture warmed on a steam bath for 15 minutes.The solution was cooled and the solid filtered ofi, washed with a littleacetone and dried to give the methobromide, M.P. 176- 180 C., (16 g.,92%).

(b) Following exactly the same procedure the ester hydrochloride, M.P.220222 C. (ct-form) was converted into a methobromide, M.P. 185186 C.(86%).

(0) Similarly, the ester hydrochloride, M.P. 199201 C. (B-form) gave acrude methobromide, M.P. 180-195" C. in quantitative yield.Recrystallisation from ethano'l/ ether gave a-methobromide, M.P.199.5-201 C.,

Example 5 This example describes the preparation of (l-methyl- 2pyrro-lidyl)methyl phenylcyclohexylglycollate methiodide.

A solution of the free base in benzene Was prepared as in Example 4(a)from the hydrochloride, M.P. 181- 196 C. Methyl iodide (2 mole) wasadded and after 24 hours at room temperature the benzene was decantedand the residual gum triturated with ethanol to give the methiodide,M.P. 179180 C. (29%).

Example 7 This example describes the preparation of (1-sthyl-2-pyrrolidyDmethyl phenylcyclohexylglycollate and its hydrochloride.

Sodium (0.1 g.) dissolved in methanol (4 ml.) was slowly added to aboiling solution of methyl phenylcyclohexylglycollate (7.7 g.) and1-ethyl-2-hydroxymethylpyrrolidine (5.0 g.) in light petroleum mL, B.P.80100 C.). The methanol that separated was collected in a Dean and Starkapparatus. After refluxing for 5 hours the solution was cooled, washedwith water and then extracted with 5N hydrochloric acid (3 x 30 ml.).The acid extracts were basified with aqueous 5N sodium hydroxidesolution and the precipitated oil extracted into ether. The etherextracts after drying were evaporated and the residual oil distilled togive (l-ethyl-Z-pyrrolidyl) methyl phenylcyclohexylglycollate (7.3 g.,66%) as a pale yellow viscous oil, B.P. -165 C./ 0.15 mm.,

-n 1.5250. The hydrochloride .was obtained in the usual way ascolourless crystals, M.P. 214215 C. (from methyl ethyl ketone).

The 1-ethyl-2-hydroxymethylpyrrolidine used in this example was obtainedby a process similar to that deg scribed in Example 1 but usingethylamine instead of methylamine.

Example 8 This example describes the preparation of (l-ethyl-Z-pyrrolidyl)methyl phenylcyclohexylglycollate ethobromide.

The free base from Example 7 was boiled under reflux for 18 hours withexcess ethyl bromide in benzene solution to give the ethobromide M.P.210-212 C., crystallised from methyl ethyl ketone.

Example 9 This example describes the preparation of 2-(1-methyl-2-pyrrolidyl)ethyl phenylcyclohexylglycollate and its hydrochloride.

This was prepared from methyl phenylcyclohexylglycollate (7.8 g.) and1-methyl-2-(2-hydroxyethyl)pyrrolidine (5.0 g.) as described in Example7 to give 2-(l'- methyl 2' pyrrolidyl)ethy1 phenylcyclohexylglycollate(7.3 g., 67%) as a viscous oil, B.P. 160 C./0.1 mm.

n 1.5261. The hydrochloride prepared in the usual way had Ml. 175-176C., crystallised from methyl ethyl ketone.

1-Methyl-2-(2-hydroxyethyl)pyrrolidine used in the above and followingexamples was obtained as follows:

Ethyldiazoacetate (35 g.) was added dropwise to a wellstirred mixture ofl methylpyrrole (70 g.) and copper bronze (3 g.) heated on a steambafll. The internal temperature of the reaction mixture was maintainedat 95l00 C. and after the addition was complete the whole was heated onthe steam bath for a further ten minutes and then filtered. The filtratewas then fractionated in vacuo (34 mm.) to give a forerun ofl-methylpyrrole (53.2 g.) and then ethyl 1-methyl-2-pyrryl-acetate as apale yellow oil (18 g.) B.P. 8488 C./ 3 mm. The yield taking intoaccount the recovered l-methylpyrrole was 51% (cf. Nenitzescu andSolomonica, Ber. 1931, 64, 1924).

Ethyl l-rnethyl-Z-pyrrylacetate (50.7 g.) in glacial acetic acid (75cc.) was hydrogenated at 45 atmospheres at room temperature for 16 hoursin the presence of a platinum oxide catalyst. The catalyst was thenremoved by filtration and the acetic acid was neutralised using aqueoussaturated potassium carbonate solution (ca. 120 cc.). Potassium acetateseparated and suificient anhydrous potassium carbonate (66 g.) was addedto saturate the aqueous layer. The inorganic material was removed byfiltration and washed with ether (4 x 50 cc.). The filtrate togetherwith the ether washing was separated and the aqueous layer Was furtherextracted with ether (4 x 250 cc.). The combined ether extracts weredried (MgS the ether removed by distillation and the residual oildistilled in vacuo, the fraction (35.5 g.), B.P. 6467 C./ 1.5 mm. beingcollected. On redistillation ethyl 1-methyl-2-pyrrolidyl acetate (34 g.,65%) was obtained as a colourless liquid, B.P. 6566 C./2.5 mm. n 1.4464(cf. $0111 and Shriner, J. Amer. Chem. Soc., 1933, 55, 3831).

Lithium aluminium hydride (3.5 g.) was added to dry ether (500 cc.)under an atmosphere of nitrogen and a solution of ethyl1-methyl-2-pyrrolidyl acetate (14.5 g.) in dry ether (50 cc.) was slowlyrun in with stirring at such a rate that the ether refluxed gently.After complete addition, (ca. 0.5 hour) the mixture was refluxed withstirring for 0.5 hour and then cooled to C. The complex was thendecomposed by the careful addition of water (18 cc.) the mixture beingstirred for 0.5 hour to ensure complete decomposition. The etherealsolution was filtered, the inorganic residue was washed with ether (4 x80 cc.) and the combined filtrate and washings dried (MgsO The ether wasremoved by distillation and the residue on distillation in vacuo gave1-methyl-2-(2- hydroxyethyl)pyrrolidine (7.1 g., 65%) as a colourlessliquid, B.P. 67 C./1.9 mm. 11 1.4698 (cf. Hess et al., Ber., 1915, 48,1886).

Example This example describes the preparation of the compoundsdescribed in Example 9 by an alternative route.

A solution of phenylcyclohexylglycollic acid (9.8 g.) and1-methyl-2(2-chloroethyl)pyrrolidine (6.2 g.) in dry isopropanol ml.)was refluxed for 16 hours. The

solvent was removed in vacuo and the residue worked up as described inExample 7, to give 2-(1'-methyl-2- pyrrolidyl)ethylphenylcyclohexylglycollate (5.9 g., 41%) as a viscous oil, B.P. 160-164C./0.1 mm. 11 1.5250. The hydrochloride had M.P. 175 C. and wasidentical with the one described in the previous example.

Example 11 This example describes the prepanation of 2-(1-methyl-2-pyrrolidyl)ethyl phenylcyclohexylglycollate methiodide.

A solution of 2-(1-methyl-2-pyrrolidyl)ethyl phenylcyclohexylglycollate(2.0 g.) and methyl iodide (1.0 ml.) in toluene ml.) was allowed tostand for several days. The toluene was then decanted and the residualgum triturated with ether to give the methiodide (2.8 g., 99%), MP.100106 C., crystallised from a mixture of ethanol and ether.

What we claim is:

1. A compound selected from the group consisting of compounds of theformula:

References Cited in the file of this patent UNITED STATES PATENTS1,987,546 Blankart Ian. 8, 1935 2,394,770 Hill et a1. Feb. 12, 19462,695,301 Blicke Nov. 23, 1954 2,790,787 Tawney Apr. 30, 1957 2,844,591Feldkarnp etal July 22, 1958 2,918,406 Biel Dec. 22, 1959 2,918,407 BielDec. 22, 1959 2,918,408 Biel Dec. 22, 1959 2,928,843 Metha et al Mar.15, 1960 FOREIGN PATENTS 483,258 Great Britain Apr. 14, 1938 624,016Great Britain May 26, 1949 OTHER REFERENCES Biel et al.: J. Am. Chem.Society, vol. 74, pages 1485-1488, (1952).

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULA: